Area 1: Discovery and validation of genetic factors influencing lung cancer risk. While several genetic loci have been identified by genome-wide scans, we hypothesize that additional loci influencing risk for lung cancer development can be identified by joint analyses in which data from multiple studies are combined. In addition, combining genotypic data will allow analysis according to demographic and clinical parameters, and permit studies to identify gene-gene and gene-environment factors that specifically increase lung cancer risk. Genetic loci that have been identified by these pooled analyses warrant further follow-up in world-wide populations to evaluate the extent that the same or other SNPs associate with lung cancer risk. Finally, follow-up studies with additfonal fine mapping and resequencing of selected populations, together with functionalanalyses, will help to identify the specific causal factors that influence cancer risk. In area 1 we are using a large and diverse population to identify genetic risk factors for lung cancer. First we will integrate 8 genome wide studies to form a pooled sample of over 13000 lung cancer cases and 25000 controls. We will perform stratified analyses to identify genes that only affect subsets of lung cancer such as early onset, and histology specific effects. We will also seek to discover significant predictors of lung cancer risk using gene-environment and gene-gene interaction analyses. Pathway analyses will also.be performed to assist in gene discovery. We will perform flne mapping and initial replication of these findings by genotyping an additional 6000 cases and 6000 controls of African-American, Chinese and Caucasian ancestry. We will finally validate our findings in an additional collection of 6000 lung cancer cases and 6000 controls. We anticipate that our studies will allow an exhaustive search of genes that have either main effects on lung cancer risk or that increase risk in combination with genetic or environmental cofactors. Our findings will be used for further functional studies in area 2 of the U19 response and epidemiological characterization in area 3 of the U19 response.